tbuckley/cabot-search huggingface dataset:
Impact of life-sustaining therapies on critically ill patients with cancer.
Authors: Kanan Shah, Joao Matos, Tristan Struja, Josef Svoboda, Leo Celi, Christopher Martin Sauer
Journal: Journal of Clinical Oncology (2023)

e13590 Background: Advances in diagnosis and treatment have led to large reductions in mortality rates for patients with cancer, resulting in a steady increase in patients admitted to intensive care units (ICUs). However, there is conflicting evidence supporting the benefit of common life-sustaining therapies for critically ill patients, within this cohort. We examined differences in treatment effects of life-sustaining therapies between critically ill septic patients with and without cancer. Methods: Adults aged 18+ with a principal cancer diagnosis from 2008 - 2019, admitted to the ICU for sepsis, were extracted from publicly accessible ICU databases: Medical Information Mart for Intensive Care IV (MIMIC-IV) and the eICU Collaborative Research Database (eICU-CRD). Logistic regression estimated the likelihood of receiving mechanical ventilation (MV), renal replacement therapy (RRT) or vasopressors (VP) during ICU admission. Additionally targeted maximum likelihood estimation (TMLE) models estimated average treatment effects of MV, VP, and RRT on mortality. As TMLE uses machine learning models, it accommodates large numbers of covariates with complex, non-linear relationships. The method outputs Average treatment effect (ATE), an odds ratio representing the mean difference in outcomes in a hypothetical world in which all patients received treatment, compared to a hypothetical world in which no patients received treatment. Models were adjusted for age, sex, ethnicity, Charlson Comorbidity Index, SOFA score, hypertension, heart failure, asthma, COPD, CKD, and code status at admission. Results: A total of 7,120 adults met inclusion criteria. Septic patients with cancer did not have a significantly different likelihood of receiving MV (aOR [95%CI], 0.94 [0.6 - 1.46]), RRT (0.79, [0.33 - 1.93]), or VP (1.09, [0.74, 1.9]) than septic patients without cancer. Among patients with low SOFA scores, those with cancer were more likely than those without cancer to benefit from RRT. Otherwise, there was no statistically significant difference in mortality with the use of MV, RRT, and VP between patients with and without cancer (p&gt;0.05). Conclusions: To our knowledge this is the first study to utilize contemporary, nationwide critical care data to establish a causal relationship between mortality and the use of common life-sustaining therapies for patients with cancer. Our study highlights the tremendous advances in cancer treatment over the last decade, leading to similar effects of common critical care interventions on mortality, regardless of cancer diagnosis. [Table: see text]
Towards the improvement of breast cancer management based on EUSOMA quality indicators: Insights from a 15-year institutional experience.
Authors: Lugo Paulina, Leticia Campoverde, Valeria Bautista, Samantha Saenz, Andres Caicedo
Journal: Journal of Clinical Oncology (2023)

e13662 Background: Breast cancer (BC) is the most common female malignancy and the leading cause of cancer-related deaths among women worldwide. Quality indicators (QIs) are evidence-based measures in healthcare used to track and improve patient care. In 2010, the European Society of Breast Cancer Specialists (EUSOMA) identified several quality indicators that could be adopted by breast cancer dedicated institutions. These QIs allow standardized clinical performance and quality assurance for BC care. We assessed the compliance of EUSOMA QIs published in 2017 by the Hospital de los Valles (HDLV), an Ecuadorian private institution, as a tool to assess BC management. This is the first project in Ecuador and South America that evaluates breast cancer quality indicators. The importance of this project is to create a foundation to identify areas for the improvement of breast cancer care in Ecuador. Methods: Women between 20 and 80 years of age with a histopathological diagnosis of BC and surgically treated at HDLV between 2007 and 2022 were included and analyzed in compliance with the updated EUSOMA QIs (2017). Exclusion criteria: male patients, breast cancer cases diagnosed by core biopsy only and without surgical excision, previous chemotherapy exposure. The number of cases meeting each criteria for EUSOMA QIs is expressed as percentages. Results: 137 women with breast cancer were included for analysis. Based on available information and resources, we were able to assess 14 out of the 34 QIs proposed by EUSOMA. Six indicators reached the minimum standard suggested by EUSOMA: 3 out of 7 QIs for diagnosis, 2 out of 3 for surgical and locoregional treatment, and 1 out of 4 for surgical and quality of life. Standards in triple diagnosis, waiting time, and surgical approaches were accomplished, while standards for surgical over-treatment and simultaneous reconstructive surgery did not meet standards. Conclusions: The lack of data about treatment, follow-up, and low access to standardized procedures limited the number of QIs assessed. This study marks a milestone towards continuous BC care improvement and indicates the need for local QIs and their regional implementation.
<i>PI3KCA</i> mutation prevalence and outcome among patients with metastatic breast cancer in Bulgaria treated with first-line endocrine therapy.
Authors: Radostina Gencheva, Savina Hadjidekova, Mila Petrova, Dimo Krustev, Petya Kraleva, Georgi Zhbantov, Nikolay Vladimirov Conev, Dragomir Svetozarov Stoyanov, Jeliazko Iliev Arabadjiev, Eliz Tazimova, Svitlana Bachurska, Ivan Galev, Mariyana Eneva, Mariela Tsvetkova, Rada Staneva, Eleonora Dimitrova, Rossen Hadjiev, Ivan Donev
Journal: Journal of Clinical Oncology (2023)

e13005 Background: There are phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha ( PIK3CA) mutations in 30-40% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2) tumor samples. Nevertheless, clinical outcomes in this group vary amongst research trials. Methods: We sought to determine the incidence of PIK3CA mutations in Bulgarian patients with metastatic HR+, HER2-negative breast cancer, as well as to evaluate and compare progression-free survival (PFS) in the real world between wild-type (WT) and mutant cohorts. In this multicentric retrospective analysis, 250 tissue samples were collected between 2016 and 2022 from three Bulgarian oncology centers. Qualitative real-time PCR was used to determine the existence of PIK3CA mutations. The median follow-up time was 28 months. Results: The mean age was 57.6±11.6 years for the mutant cohort and 56.5±12.2 for the wild-type cohort (p=0.52). The percentage of patients with visceral metastatic disease was 58.8% (n=147). Postmenopausal patients were 84.3% (n=210). PIK3CA mutation prevalence was 29.2% (n=73). The most prevalent mutation was found in exon 20: H1047R (9.2%). Among all clinicopathological features, we observed only a significant relation between the presence of a mutation and a metastatic stage at diagnosis (p = 0.002). 67.1% of the patients received endocrine therapy (ET) + CDK4/6 inhibitor as first-line therapy, while the remainder receive ET monotherapy. Patients with PIK3CA mutation did not have significantly different median PFS compared to WT patients (32 months (95%, CI: 22-40) versus 24 months ((95%, CI: 21-36) (p=0.45)); HR=0.86 (95%, CI: 0.5-1.3) (p=0.46). In propensity matching score analysis (matched for treatment utilized as a first line ET, menopausal status, and locations of metastatic disease), we confirmed our finding (36 months (95%, CI: 20-40) versus 26 months (95%, CI: 21-38), p = 0.69). Conclusions: We demonstrated that the prevalence of PIK3CA mutations in Bulgarian patients is comparable to that reported in other countries. Our findings suggest that the presence of a PIK3CA mutation has no effect on the efficacy of endocrine therapy of first-line treatment. In summary, our study provides valuable insights into the topic, but limitations including the retrospective design and small sample size suggest that the findings need to be replicated by more robust studies and larger sample sizes to draw definitive conclusions.
Refractory colorectal cancer patient derived MicroOrganoSpheres (MOS) to enable correlation of targeted therapy combination response with clinical outcomes.
Authors: Shengli Ding, Preeti Kanikarla Marie, Nicholas Baro, Renuka Raman, Elena Helman, Shiaowen David Hsu, Scott Kopetz, Xiling Shen
Journal: Journal of Clinical Oncology (2023)

e15574 Background: Metastatic colorectal cancer (CRC) patients who have become resistant to standard-of-care (SOC) treatments are often put on targeted therapies, including experimental drugs still in clinical trials. However, patients with targeted mutations still often do not respond to the targeted therapies alone, hence it remains a critically unmet need to explore potential combinatorial regimens that will enhance the efficacy. Methods: We performed a high-throughput screen using MicroOrganoSpheres (MOS) derived from metastatic refractory patients to correlate with clinical outcomes and explore alternative combinations that might benefit the patients. Biopsies from metastatic CRC patients who became resistant to SOC and were about to receive targeted therapies in clinical trials were molecularly profiled and implanted into immunodeficient mice to generate patient-derived xenografts (PDX). Results: MOS were derived and established from PDX using droplet-based microfluidics for high-throughput 3D screening. These MOS-based refractory patient avatars contain either targetable mutations including KRAS G12C and BRAF 600E or no such mutations. Response of the MOS to dose-titrated single and combination drug treatments including the available targeted therapies were measured by a fully automated robotic dispensing and imaging pipeline and quantified by AI-based live imaging analytical algorithm to generate robust drug response curves, which were used to derive IC50 and EC50. We tested both FDA-approved and experimental targeted therapies as single agent or in combination in 5-dose titrations. Longitudinal tracking of each MOS with Live/dead fluorescence dye signals was obtained for 5 days. MOS drug response curves and IC50s show correlation with clinical outcomes. This comprehensive dataset enabled us to assess the potential benefit of different combinations, help deconvolute the efficacy and synergy of individual drugs, and provide insight into patients who fail to response to targeted therapies despite possessing the targeted mutations. As the MOS diagnostic assay can be completed from a patient biopsy within 10 days and is currently in a registered, multi-site clinical trial (ClinicalTrials.gov # NCT05189171), this study provides proof-of-principle for a potential clinical MOS-based assay to guide refractory patients to the optimal combination regimen containing targeted therapy. Conclusions: Refractory patients may benefit from a MOS-based high-throughput screen assay to select the optimal combination regimen containing targeted therapy.
Phase I study of the bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 combined with SHR2554, an EZH2 inhibitor, in patients with previously treated advanced lymphoma and solid tumors.
Authors: Kaichao Feng, Yang Liu, Chunmeng Wang, Jing Nie, Yan Xia, Jingting Jiang, Weidong Han
Journal: Journal of Clinical Oncology (2023)

2507 Background: Despite the remarkable successes of cancer immunotherapies, the majority of patients (pts) experience only partial response and most pts will progress. Enhancer of zeste homolog 2 (EZH2) as an epigenetic target for cancer therapy has been shown to enhanced antigen presentation and synergize with immunotherapy in preclinical studies. This study investigates the safety and efficacy of SHR-1701 (anti-PD-L1/TGF-βRII) plus SHR2554 (EZH2i) in pts with pretreated advanced lymphoma and solid tumors. Methods: This open-label, single-arm, phase 1 study enrolled pts with pretreated advanced lymphoma and solid tumors. Escalating doses of SHR2554 (300–350mg bid) plus fixed-dose SHR-1701 (30mg/kg q3w) were evaluated in the dose-escalation phase. SHR2554 at the recommended phase 2 dose (RP2D) plus SHR-1701 were administered in the dose-expansion phase. The primary end point was determination of the RP2D of SHR2554 plus SHR-1701. Secondary end points included safety and preliminary activity. Results: By January 6, 2023, 33 patients were enrolled (dose-escalation: n=7; dose-expansion, n=26). No dose-limiting toxicities were observed, and RP2D was established as SHR2554 350mg bid plus SHR-1701 30mg/kg q3w. Treatment-related adverse events (TRAEs) occurred in 13 of 32 patients (40.6%), mainly including platelet count decreased (21.9%), anemia (15.6%) and vomiting (15.6%). The most common Grade ≥3 TRAEs were anemia (3.1%) and fever (3.1%). In the efficacy-evaluable population (n = 26), objective response rate (ORR) was 57.7%, including 2 complete response (CR) achieved by patients with Metastatic Renal Cell Carcinoma and classical Hodgkin lymphoma (cHL). 16 patients with relapsed/refractory classical Hodgkin lymphoma (cHL) after a median of 10 prior lines of therapy have been enrolled. 16 (100%) cHL pts had received prior anti-PD1/PD-L1 antibody therapy, and 15 ( 93.8%) prior epigenetic therapies, such as decitabine or chidamide. Out of 14 cHL-evaluable patients, ORR was 100% and the CR rate was 7.1%. Conclusions: SHR-1701 combined with SHR2554 showed acceptable safety profile and encouraging antitumor activity in immunotherapy-pretreated cHL, establishing the foundation for further exploration. Clinical trial information: NCT04407741 .
An engineered Trop2/CD3 bispecific antibody for treatment of gastric, pancreatic, and colorectal cancers.
Authors: Diana O, Kronos Chow, Deepak Iyer, Monarca Wong, Tony K Wong, Dennis A Wong, John Moon Luk
Journal: Journal of Clinical Oncology (2023)

e14521 Background: Given its over-expression and poor prognosis in a variety of solid tumors, trophoblast cell surface antigen 2 (Trop2) is regarded as a potential therapeutic target. Trop2-directed antibody-drug conjugates have been developed for treatment of solid tumors; however, their clinical benefits can be limited by the associated undesirable effects which is likely attributed to the on-target off-tumor effect arising from the low basal Trop2 expression on the surface of multiple normal epithelial tissues. The present study aims to develop a humanized Trop2/CD3 bispecific T-cell engager antibody that can promote immunological synapse formation with tumor cells overexpressing Trop2, redirecting T cell-mediated killing specifically to cancers with reduced risk of on-target off-tumor effects. Methods: A Trop2/CD3 bispecific antibody was generated by linking a humanized anti-Trop2 monoclonal antibody with a CD3-binding scFv. To tune the affinity of the bispecific antibody for tumor target, in silico paratope prediction was firstly done using ProABC-2 (Ambrosetti F et al., 2020), following by alanine substitution of the identified paratope residues individually. A total of 6 CDR variants were generated with their binding to Trop2 examined using biolayer interferometry. Selected candidates were further characterized for their binding to Trop2-positive cancer cells and activation of T cells upon target engagement. Redirection of T cell-mediated killing on cancer cells expressing high Trop2 level was also studied in vitro. Results: Substitution of a complementarity-determining residue (CDR) on the heavy chain of anti-Trop2 antibody with an alanine significantly reduced binding affinity to Trop2. This CDR variant was selected for further functional characterization. Apart from weaker binding to Trop2-positive tumor cells, the variant also demonstrated a slower cytokine induction, a less acute T-cell activation, and a cytotoxic effect which was more restricted to Trop2-high cancer cells. Conclusions: Our new Trop2/CD3 bispecific antibody demonstrates potent anti-tumor activity, while at the same time shows a reduced risk of on-target off-tumor toxicity. The drug candidate warrants further investigations including toxicity study in monkeys. [Table: see text]
Cost of care associated with utilization of telehealth in clinical trials.
Authors: Emily Gleason, Elizabeth Tubridy, Leslie Andriani, Destiny Uwawuike, Simon Gunter, Nathanael Koelper, Heidi Harvie, Emily Meichun Ko
Journal: Journal of Clinical Oncology (2023)

e13682 Background: Due to COVID-19 pandemic restrictions, telehealth was incorporated into standard oncologic care and clinical trials. Existing data show that telehealth in clinical trials is safe, feasible, and reduces barriers to participation. We sought to analyze whether telehealth changed the cost of care compared to traditional clinical trial operations. Methods: We conducted a retrospective cohort study of gynecologic oncology patients enrolled in therapeutic clinical trials at a NCCN designated cancer center, comparing health care reimbursement cost of care on trial pre-TELEhealth (9/30/2019 to 3/15/2020) with those during TELEhealth (3/16/2020 to 8/20/2020). Inclusion required trial enrollment during both study periods, at least 1 telehealth visit, and identifiable billing records. Health care costs were collected. Cost data included: 2020 Medicare reimbursements for procedures, provider billing, DRG for hospital admissions, drug average sales price, and GoodRx for outpatient prescriptions. Encounters unrelated to cancer care were excluded. Overall cost per patient and patient-per-month on trial were calculated for scheduled (per protocol) and unscheduled (non-protocol) encounters. Pairwise t-tests between pre-TELE and TELE periods were performed. Results: 28 patients were included (86% White, 7% Black, 6% other) with 26 (93%) ovarian, 1 (4%) uterine, and 1 (4%) concurrent ovarian/uterine cancer. The majority (89%) had stage 3 or 4 cancer at diagnosis. Overall care utilization was similar in pre-TELE and TELE periods, with 292 vs. 321 scheduled visits, and 31 vs. 37 unscheduled visits. Mean total cost per patient was similar in pre-TELE and TELE periods, including scheduled encounters ($15794.58 (SD 17719.92) vs. $20714.47 (SD 25338), p= 0.118) and unscheduled encounters ($759.96 (SD 2066.72) vs. $2911.71 (SD 6060.18), p=0.080). Per month on trial, mean cost per patient did not differ. No differences were seen in total scheduled or total unscheduled encounters, nor office visits, admissions, ED visits and outpatient procedures. Conclusions: Incorporation of telehealth in gynecologic cancer clinical trials did not increase cost of scheduled or unscheduled care. Telehealth is a critical component to decentralizing clinical trials, reducing barriers to trial participation and improving the value of cancer care. [Table: see text]
Human epidermal growth factor receptor 2/3 (HER2/HER3) expression in higher-grade meningioma.
Authors: Maximilian Mair, Erwin Tomasich, Christina Paiato, Georg Widhalm, Franziska Eckert, Felix Sahm, Johannes A. Hainfellner, Anna Sophie Berghoff, Matthias Preusser
Journal: Journal of Clinical Oncology (2023)

e14063 Background: Meningiomas are the most frequently diagnosed primary central nervous system (CNS) tumors in adults. Although most meningiomas can be cured by resection, higher-grade lesions (CNS WHO grades 2 &amp; 3) tend to recur, with limited systemic treatment options after exhaustion of local therapies. Antibody drug conjugates (ADCs) targeting human epidermal growth factor receptors 2 and 3 HER2/HER3) have shown remarkable clinical activity in solid tumors including breast cancer brain metastases and are under investigation in various malignancies. Methods: 64 patients with WHO grade 2 (atypical) and 3 (anaplastic) meningioma have been included. DNA methylation analysis has been performed using Illumina EPIC methylation arrays. Panel sequencing for NF2, PIK3CA, SMO, ARID1A, ARID1B, KLF4, SUFU, TERT promotor, and TRAF7 has been executed applying the Illumina NextSeq 500 platform. HER2 and HER3 expression was evaluated by immunohistochemical analysis using PATHWAY HER2 (4B5, Roche) and HER3 #12708 (Cell Signaling) antibodies on a Ventana Benchmark Ultra staining system. Results: In total, 44/64 (68.8%) patients with WHO grade 2 and 20/64 (31.2%) patients with WHO grade 3 meningioma were included. Median age at surgery was 60 years (range: 19-83), and 37/64 (57.8%) patients were female. DNA methylation classes according to the Molecular Neuropathology classifier were benign-1 in 10 (15.6%), benign-2 in 10 (15.6%), benign-3 in 4 (6.3%), intermediate-A in 26 (40.6%), intermediate-B in 4 (6.3%), and malignant in 10 (15.6%) out of 64 tumors. Weak membranous HER2 expression was observed in 1/64 (1.6%) tumor, which was categorized as WHO grade 3/intermediate-B meningioma characterized by infiltration of adjacent bone and fat tissue as well as positive Ki-67 staining of up to 39% of cells. Similarly, only one sample (1.6%) was HER3-positive which was diagnosed as WHO grade 2 tumor of methylation class benign-2, showing meningothelial morphology with elevated mitotic activity and a mutation in TRAF7. The single HER2+ as well as the HER3+ sample were from two distinct female patients. Conclusions: In our cohort, HER2 and HER3 were only infrequently expressed in a small subset of samples of different WHO grade, methylation class, and genetic background. Exploration of further targets of ADCs which are approved or under investigation in other tumors is currently ongoing.
Tele-oncology implementation logic model.
Authors: Amir Alishahi Tabriz, Kea Turner, Cristina Naso, Brian D. Gonzalez, Laura B. Oswald, Oliver Nguyen, Julie E. Hallanger-Johnson, Krupal Patel, Young-Rock Hong, Byron J Powell, Philippe E. Spiess
Journal: Journal of Clinical Oncology (2023)

e13681 Background: The onset of the coronavirus disease 2019 (COVID-19) pandemic changed the landscape of oncology practice and placed tele-oncology at the center of cancer care delivery. As tele-oncology will likely remain a key part of cancer care delivery, healthcare organizations need to determine how to implement tele-oncology programs. We conducted an instrumental case study at a National Cancer Institutes -designated comprehensive cancer center that successfully implemented tele-oncology. Methods: Data were collected from three sources between June 2020–February 2022. We conducted semi-structured interviews among stakeholders directly involved in implementing and/or managing tele-oncology and surveys of administrators of the center’s tele-oncology and clinicians who used the program. Document analysis of implementation deliverables were also analyzed. Data collection and analyses were guided by the Consolidated Framework for Implementation Research, and Clinical Transformation in Technology. We used the Implementation Research Logic Model (IRLM) to develop a framework depicting determinants and key steps for implementing tele-oncology. Results: We interviewed 40 clinicians. We also invited 364 employees to complete online surveys, of which 151 (41.5%) responded. Most respondents were physicians (41.7%), nurse practitioners (26.5%), or physician assistants (26.5%). To implement tele-oncology program, three elements should be considered: (1) platform, (2) people, and (3) process. We found hospitals should: 1) adopt a safe and adaptable platform to deliver tele-oncology; 2) build a multidisciplinary tele-oncology team to provide the administrative, legal, workflow, and clinical support; 3) provide training and resources to make sure all the team members can deliver their responsibilities; 4) identify and appreciate early adopters, departments, and clinicians with successful experiences; 5) frequently evaluate the clinical and implementation outcomes; 6) secure reimbursement comparable with in-person rate and ; 7) advocate for policies that are supportive of tele-oncology in the future. Conclusions: Using IRLM we presented the tele-oncology implementation framework that can be used by hospitals around the world to implement their own tele-oncology.